rs772894995

Variant names:

• chr19-11061816-A-G
• rs772894995
• NM_001387283.1:c.5040A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-11061816-A-G
• chr19-11061816-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001387283.1(SMARCA4):​c.5040A>G​(p.Ter1680Trpext*?) variant causes a stop lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_001387283.1 stop_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.28
• Publications: 0 publications found

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001387283.1 Downstream stopcodon found after 1736 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.5040A>G	p.Ter1680Trpext*?	stop_lost	Exon 36 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4944A>G	p.Ter1648Trpext*?	stop_lost	Exon 35 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.5040A>G	p.Ter1680Trpext*?	stop_lost	Exon 36 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4944A>G	p.Ter1648Trpext*?	stop_lost	Exon 35 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4950A>G	p.Ter1650Trpext*?	stop_lost	Exon 35 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4854A>G	p.Ter1618Trpext*?	stop_lost	Exon 35 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4854A>G	p.Ter1618Trpext*?	stop_lost	Exon 34 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4854A>G	p.Ter1618Trpext*?	stop_lost	Exon 34 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4851A>G	p.Ter1617Trpext*?	stop_lost	Exon 35 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4365A>G	p.Ter1455Trpext*?	stop_lost	Exon 32 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3594A>G	p.Ter1198Trpext*?	stop_lost	Exon 28 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3576A>G	p.Ter1192Trpext*?	stop_lost	Exon 27 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3438A>G	p.Ter1146Trpext*?	stop_lost	Exon 27 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3204A>G	p.Ter1068Trpext*?	stop_lost	Exon 25 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.1008A>G	p.Ter336Trpext*?	stop_lost	Exon 8 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251194 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Feb 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 486471). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (rs772894995, gnomAD 0.002%). This sequence change disrupts the translational stop signal of the SMARCA4 mRNA. It is expected to extend the length of the SMARCA4 protein by 19 additional amino acid residues. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 02, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5040A>G variant (also known as p.*1680Wext*19) is located in coding exon 35 of the SMARCA4 gene, and results from an A to G substitution at nucleotide position 5040, which is the last nucleotide of the SMARCA4 gene. The stop codon at position 1680 is replaced by tryptophan, resulting in an elongation of the protein by 19 amino acids. The exact functional impact of these inserted amino acids is unknown at this time. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 100000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Benign	0.76
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.3
Vest4		0.45
GERP RS		4.3
Mutation Taster		=69/131	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs772894995; hg19: chr19-11172492;